Does CRRT Improve Renal Recovery and Outcomes?

UK Kidney Research Keynote Lecture

Patrick D Brophy, MD, MHCDS

Director Pediatric Nephrology

Professor

The University of Iowa

London 2015

UnEqual

Many questions remain unanswered

• What therapy should we use?• When should we start it?• What are we trying to achieve?• How much therapy is enough?• When do we stop/switch?• Can we improve outcomes?• Throughout the conference these are

the basic questions we have tried to address!

Overview

• Impact of Acute Kidney Injury in the PICU• Therapies Comparison in brief

– IRRT, CRRT & Hybrid therapies -SLEDD• Solute clearance with IRRT v CRRT v SLEDD• Dose-outcome relationships & IRRT v CRRT• Summary & thoughts

Pediatric AKI: Definition

Past: So many definitions….

Risk Injury Failure End-Stage Kidney Disease (RIFLE)

Pediatric RIFLE (pRIFLE)

Acute Kidney Injury Network definition

Crit Care. 2005; 9(5): 523–527

Pediatric AKI: Incidence in PICUPopulation & Definition-dependent

Cardiac Surgery

Kidney Int. 2009 Oct;76(8):885-92 Anesth Analg 2009;109:45–52(Aprotinin study)

N = 395 N=395

AKI: 21%AKI: 34%

Pediatric AKI: Incidence in PICUPopulation & Definition-dependent

General PICU

Pediatr Crit Care Med 2007; 8:29 –35 Al-Kandari et al, ASN, 2008

Kid Int 2007; 71: 1028-35

82% AKI4.5% AKI 42% AKI

Most Critically ill childrenVasopressors/VentilatedUrinary catheter

pRIFLE

All PICU Admx SCr baseline

SCr Doubling (pRIFLE I)

All PICU stay>48hrs

pRIFLE

Pediatric AKI: Changing Epidemiology

Pediatric ARF Causes

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Stickle SH et al: Am J Kid Dis 45:96-101, 2005

Previously: Primary renal diseases

CRRT Diagnoses

RRT Options

Hemodialysis, Peritoneal Dialysis, CRRT, SLEDD Each has advantages & disadvantages Choice is guided by

Patient Characteristics o Disease/Symptomso Hemodynamic stability

Goals of therapyo Fluid removalo Electrolyte correctiono Both

Availability, expertise and cost

Pediatr Nephrol (2009) 24:37–48

Trends in Pediatric RRT

Warady et al, Pediatr Neph 2000, 15:11-3

CRRT Increasing 12-US Multicentre ppCRRTMost include Dialysis

Why CRRT?

Reduces hemodynamic instability preventing secondary ischemia Precise Volume control/immediately adaptable Uremic toxin removal Effective control of uremia, hypophosphatemia,

hyperkalemia Acid base balance

Rapid control of metabolic acidosis Electrolyte management

Control of electrolyte imbalances Allows for improved provision of nutritional support Management of sepsis/plasma cytokine filter Safer for patients with head injuries

Indications for Pediatric RRT

Electrolyte (metabolic) imbalance Uremia with bleeding and or

encephalopathy Acuity/Degree of Kidney Injury

reduction in GFR/elevated creatinine

reduction in urine output Nutritional support Intoxications, Inborn errors of

Metabolism (IEM)

Fluid Overload (hypervolemia with pulmonary edema/respiratory failure)

Implications of the available data

Major Renal Replacement Techniques

Intermittent ContinuousHybrid

IHDIntermittent

haemodialysis

IUFIsolated

Ultrafiltration

SLEDDSustained (or

slow) low efficiency daily

dialysis

SLEDD-FSustained (or

slow) low efficiency daily

dialysis with filtration

CVVHContinuous veno-

venous haemofiltration

CVVHDContinuous veno-

venous haemodialysis

CVVHDFContinuous veno-

venous haemodiafiltration

SCUFSlow continuous

ultrafiltration

Intermittent Therapies - PRO

Intermittent Therapies - CON

Intradialytic Hypotension: Risk Factors

• Age < 5, weight < 10 kg• Pressor requirement, Low Predialysis SBP • Cardiac disease- congenital repairs• Poor nutritional status / hypoalbuminaemia• Uremic neuropathy or autonomic dysfunction• Severe anemia• High volume ultrafiltration requirements

Managing Intra-dialytic Hypotension

Dialysate temperature modelingLow temperature dialysate

Dialysate sodium profilingHypertonic Na at start decreasing to 135 by endPrevents plasma volume decrease

Midodrine if not on pressorsUF profilingColloid/crystalloid bolusesReducing dosing

2005 National Kidney Foundation K/DOQI GUIDELINES

Continuous Therapies - PRO

** Depends on strategy and management

Continuous Therapies - CON

SLED(D) & SLED(D)-F : Hybrid therapy

Conventional dialysis equipment Online dialysis fluid preparation Excellent small molecule detoxification Cardiovascular stability maybe as good

as CRRT Reduced anticoagulation requirement Decreased costs compared to CRRT? Phosphate supplementation required like

CRRT

Fliser, T & Kielstein JT. Nature Clin Practice Neph 2006; 2: 32-39 Berbece, AN & Richardson, RMA. Kidney International 2006; 70: 963-968

Uremia Control

Liao, Z et al. Artificial Organs 2003; 27: 802-807

Large molecule clearance

Liao, Z et al. Artificial Organs 2003; 27: 802-807

Comparison of IHD and CVVH

John, S & Eckardt K-U. Seminars in Dialysis 2006; 19: 455-464

RRT for Acute Kidney Injury

• There is some evidence for a relationship between higher therapy dose and better outcome, at least up to a point

• This is true for IHD* and for CVVH**• There is no definitive evidence for superiority

of one therapy over another, and wide practice variation exists***

• Accepted indications for RTT vary• No definitive evidence on timing of RRT

*Schiffl, H et al. NEJM 2002; 346: 305-310 ** Ronco, C et al. Lancet 2000; 355: 26-30*** Uchino, S. Curr Opin Crit Care 2006; 12: 538-543

Therapy Dose in IRRT

p = 0.01

p = 0.001

Schiffl, H et al. NEJM 2002; 346: 305-310

The “Ronco Study”Improved survival

in all patients with convective clearance of 35mL/kg/hr

Trend towards improved survival in septic patients with convective clearance of 45mL/kg/hrRonco, C et al. Lancet 2000; 355: 26-30

Therapy Dose in CVVH

The “ATN Study” 1124 adults in the ICU

563 had intensive therapy 561 had less-intensive therapy

ATN Study

ATN Study

Intensity of CRRT in Critically Ill Patients (The “RENAL” Study)

NEJM 361(17); Oct 2009

NEJM 361(17); Oct 2009

Intensity of CRRT in Critically Ill Patients (The “RENAL” Study)

Outcome with IRRT vs CRRT

Trial quality low: many non-randomized

Therapy dosing variable

Illness severity variable or details missing

Small numbers Uncontrolled

technique, membrane Definitive trial would

require 660 patients in each arm!

Unvalidated instrument for sensitivity analysis

Kellum, J et al. Intensive Care Med 2002; 28: 29-37

“there is insufficient evidence to establish whether CRRT is associated with improved survival in critically ill patients with ARF when compared with IRRT”

Outcome with IRRT vs CRRT

Tonelli, M et al. Am J Kidney Dis 2002; 40: 875-885

• No mortality difference between therapies• No renal recovery difference between

therapies• Unselected patient populations• Majority of studies were unpublished

Outcome with IRRT vs CRRT

Vinsonneau, S et al. Lancet 2006; 368: 379-385

Summary

There is some evidence for a relationship between higher therapy dose and better outcome for IHD

There is no definitive evidence for beneficial effects of high dose CRRT despite major attempts to do so

Trials have demonstrated it is difficult to deliver this dose due to unpredictable breaks in treatment-clotting, bag changes, nursing (Vesconi 2009)

Modern IHD approaches may reduce overt hemodynamic instability even in unstable ITU patients

CRRT greater exposure to anticoagulation

*Schiffl, H et al. NEJM 2002; 346: 305-310 ** Ronco, C et al. Lancet 2000; 355: 26-30*** Uchino, S. Curr Opin Crit Care 2006; 12: 538-543

Summary

RCT (Uchino 2009) 3-5% incidence of significant bleeding problems as opposed to 1% with IHD

HIT

Filter downtime up to 8 hours per day due to clotting problems and short filter life

Delayed procedures, tests,surgery

The legion of alternatives used emphasize the problem **citrate looks promising

Costs– although this is variable (Srisawat N et al. Crit Care. (2010))

DeathDeath

Approach to Pediatric AKI

NormalNormal Increasedrisk

Increasedrisk

Kidneyfailure

KidneyfailureDamageDamage GFR GFR

AntecedentsIntermediate StageAKIOutcomes

EGDT

Defend Blood PressureRestore & Optimize PerfusionUse inotropes with careMitigate Inflammatory Injury

Optimize RRT

Reference Tools

Adqi.net-web site for information on CRRT Crrtonline.com-web site for info on Dr Mehta’s meeting www.PCRRT.com Pediatric CRRT with links to other meetings,

protocols, industry PCRRT list serve (contact Bunchman)